CD85/LIR-1/ILT2 and CD152 (cytotoxic T lymphocyte antigen 4) inhibitory molecules down-regulate the cytolytic activity of human CD4(+) T-cell clones specific for Mycobacterium tuberculosis

Antigen-specific cytolytic CD4(+) T lymphocytes control Mycobacterium tuber culosis infection by secreting cytokines and by killing macrophages that ha ve phagocytosed the pathogen. However, lysis of the latter cells promotes m icrobial dissemination, and other macrophages engulf the released bacteria. Subsequently, CD4(+) T-cell-mediated killing of macrophages goes on, and t his persistent process may hamper control of infection, unless regulatory m echanisms maintain a subtle balance between lysis of macrophages by cytolyt ic CD4(+) cells and activation of cytolytic CD4(+) cells by infected macrop hages. We asked whether inhibitory molecules expressed by CD4(+) cytolytic T lymphocytes could play a role in such a balance. To this end, human CD4() T-cell clones specific for M. tuberculosis were produced that displayed a n autologous major histocompatibility complex class II-restricted lytic abi lity against purified protein derivative (PPD)-pulsed antigen-presenting ce lls. All T-cell clones expressed CD152 (cytotoxic T-lymphocyte antigen 4 [C TLA-4]) and CD85/leukocyte immunoglobulin-like receptor 1 (LIR-1)/immunoglo bulin-like transcript 2 (ILT2) inhibitory receptors, but not CD94 and the k iller inhibitory receptor (or killer immunoglobulin-like receptor [KIR]) p5 8.2. CD3-mediated activation of the clones was inhibited in a redirected ki lling assay in which CD152 and CD85/LIR-1/ILT2 were cross-linked. Specific antigen-mediated proliferation of the clones was also sharply reduced when CD152 and CD85/LIR-1/ILT2 were cross-linked by specific monoclonal antibody (MAb) followed by goat anti-mouse antiserum. In contrast, blockade of the receptors by specific MAb only increased their proliferation. Production of interleukin 2 (IL-2) and gamma interferon (IFN-gamma) by the T-cell clones was also strongly reduced when CD152 and CD85/LIR-1/ILT2 were cross-linked . The lytic activity of the T-cell clones against PPD-pulsed autologous mon ocytes or Epstein-Barr virus-activated B cells was increased by blockade an d decreased by cross-linking of the receptors. These results indicate that CD152 and CD85/LIR-1/ILT2 play a role in the regulation of the antigen-spec ific activity of CD4(+) cytolytic T lymphocytes against PPD-presenting cell s.